PROJECT SUMMARY ? Project 2 We aim to explore the alterations that arise on peanut epitope-specific T-cell repertoires in response to immunotherapy. This work will take advantage of a cohort of food allergy patients, available to this project, that display a wide variety of responses to food challenge and to interventional therapy. These include food allergic patients who differ in clinical manifestation at baseline, patient non- responder to therapy, patients who experience adverse reactions during therapy, patients that loss peanut sensitization during therapy but not at the end of an avoidance period and patient that gain long term tolerance to peanut as a result of immunotherapy. This investigation will be performed in the context of an Immune Tolerance Network funded Peanut Oral Immunotherapy trial and in the context of an Aravax funded peanut specific peptide immunotherapy trial. Both effector T cells and regulatory T cells will be examined and we will capitalize on epitope discovery from project 1 to probe peanut allergen epitope specific T cells. The proposed work will include the use of state-of art technologies such as pMHCII tetramer staining and dual CD154/CD137 assay allowing determination of the contribution of allergen epitope-specific T cells to the global peanut specific T cell responses. We will also explore the alterations that arise on TCR repertoire and transcriptional phenotype of peanut-specific T cells during clinical intervention. These information are pertinent for determining suitable target to guide the design of optimal allergy vaccines. We will finally determine the extent to which these T cell epitopes can be used as biomarker predicting which patients are most likely to benefit from these therapeutic interventions, which immune mechanisms are involved and screen out those candidates in whom immunotherapy may lead to unnecessary risks.